Elsevier

The Lancet

Volume 385, Issue 9974, 28 March–3 April 2015, Pages 1198-1205
The Lancet

Articles
P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study

https://doi.org/10.1016/S0140-6736(14)61255-1Get rights and content

Summary

Background

Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough.

Methods

We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730.

Findings

Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219.

Interpretation

P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives.

Funding

Afferent Pharmaceuticals

Introduction

Cough is the most common symptom that causes patients to seek medical advice in the USA.1 Cough disrupts patients' lives with physical, social, and psychological effects,2 yet effective, safe, and well tolerated antitussive treatments are an important unmet clinical need. Although most patients seeking treatment have a transient cough associated with viral upper respiratory tract infections, up to 12% of people might have chronic coughing, defined as a cough that lasts longer than 8 weeks.3

Chronic cough is associated with many pulmonary disorders (eg, asthma, chronic obstructive pulmonary disease, lung cancer, and interstitial lung disease), some drugs (eg, angiotensin-converting-enzyme [ACE] inhibitors), and extrapulmonary disorders such as nasal disease and gastro-oesophageal reflux disease (reflux).4 Asthma, reflux, and nasal disease are thought to be the most common causes of chronic cough in patients with normal chest radiological findings and clinical assessments,5 but most patients with asthma, reflux, or nasal disease do not have cough. This finding would suggest that additional pathological processes occur, leading to the excessive coughing. The recent published work suggests an increasing proportion of these patients are refractory to treatment of any underlying disorders, despite careful investigation and trials of treatments.6 In such patients, few treatment options are available.

The afferent fibres that evoke cough are almost completely confined to the vagus nerve and preclinical studies suggest key roles for both C fibres (chemoreceptors) and Aδ fibres (mechanoreceptors).7 P2X3 receptors are ATP-gated ion channels selectively localised on populations of primary afferent nerves arising from both cranial and dorsal root ganglia.8, 9 In guinea pigs, vagal C fibres innervating the airways express P2X3 receptors, and can be activated by ATP released into the airways.10, 11 Moreover, when guinea pigs are exposed to ATP and histamine aerosols, cough responses to tussive stimuli are increased via P2X-receptor-mediated mechanisms.12, 13

Patients with chronic cough frequently report coughing evoked by several environmental exposures—eg, temperature change, perfumes, and smoke.14 Experimentally, these patients also have heightened cough responses to a range of inhaled tussive agents including capsaicin,15 citric acid,16 hypertonic saline,17 and mannitol.18 Together, these observations imply a generalised hyperexcitability of the cough reflex that could result from changes in the afferent nerves or central pathways. P2X3-receptor activation could enhance responsiveness to a broad range of stimuli, either through the priming of sensory afferent nerve terminals in airways or modulation of activity at their central synapses.8, 19, 20 We aimed to test whether P2X3 receptors have a role in cough reflex hyper-responsiveness. We report the results of a proof-of-concept phase 2 study of AF-219, a first-in-class P2X3 antagonist, in patients with refractory chronic cough.

Section snippets

Study design and participants

We did a randomised, double-blind, placebo-controlled, two-period crossover study at the North West Lung Centre at the University Hospital of South Manchester (Manchester, UK). We recruited adults with refractory chronic cough (>8 weeks' duration) attending a specialist cough clinic (between Sept 22, 2011 and Nov 29, 2012). All patients had previously undergone investigations and treatment trials to exclude possible underlying causes of chronic cough, as stated in British Thoracic Society

Results

34 patients were screened; 24 patients were randomly assigned to treatment sequences after exclusion criteria were applied (figure 1, table 1). Excluding an outlying patient with a very high frequency of coughing (daytime frequency of 767 coughs per h), mean baseline daytime cough frequency was 39·1 coughs per h (SD 31·4) and night-time frequency was 4·2 coughs per h (SD 7·0). Six patients withdrew during treatment (figure 1), all because of adverse events while taking AF-219; four withdrew on

Discussion

Our study is the first to assess the efficacy of a P2X3 antagonist in any disease (panel), and is also the first to verify meaningful reductions in cough frequency by 24 h ambulatory acoustic cough monitoring. During treatment with AF-219, many patients had unprecedented improvements in daytime cough frequency and these changes, measured objectively via cough recordings, were accompanied by improvements in patient-reported outcomes, including ratings of cough severity, urge to cough,

References (35)

  • NM Ryan et al.

    Gabapentin for refractory chronic cough: a randomised, double-blind, placebo-controlled trial

    Lancet

    (2012)
  • OK Basoglu et al.

    Effects of aerosolized adenosine 5'-triphosphate vs adenosine 5'-monophosphate on dyspnea and airway caliber in healthy nonsmokers and patients with asthma

    Chest

    (2005)
  • SM Schappert et al.

    Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 2001–02

    Vital Health Stat 13

    (2006)
  • AC Ford et al.

    Cough in the community: a cross sectional survey and the relationship to gastrointestinal symptoms

    Thorax

    (2006)
  • BJ Canning et al.

    Cough sensors. I. Physiological and pharmacological properties of the afferent nerves regulating cough

    Handb Exp Pharmacol

    (2009)
  • G Burnstock et al.

    Purinergic signaling in the airways

    Pharmacol Rev

    (2012)
  • K Kwong et al.

    P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating guinea pig lungs and esophagus

    Am J Physiol Lung Cell Mol Physiol

    (2008)
  • Cited by (0)

    View full text